Immune Milieu Established by Postpartum Liver Involution Promotes Breast Cancer Liver Metastasis.
Immune Milieu Established by Postpartum Liver Involution Promotes Breast Cancer Liver Metastasis.
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产后肝复旧建立的免疫环境促进乳腺癌肝转移。
DOI：
10.3390/cancers13071698
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发表时间：
2021-04-03
期刊：
影响因子：
5.2
通讯作者：
Schedin P
中科院分区：
文献类型：
--
作者：
Bartlett AQ;Pennock ND;Klug A;Schedin P
当癌症转移到继发部位时，它就会变得致命，对于乳腺癌来说，肝脏转移是一个严重的临床问题。肝转移的部分原因是肝脏环境的改变，导致形成支持循环肿瘤细胞的转移生态位。了解肝脏生态位如何支持乳腺癌细胞，可能会导致转移性乳腺癌患者的治疗方法的发展。在这里，我们报告了发育调节的断奶诱导的肝脏退化过程增加了癌细胞中的肝转移，否则转移潜力较低。肿瘤转移的增加与消退肝脏的独特免疫学特性有关，包括激活肿瘤细胞清除所需的T细胞的能力降低。这些数据建立了生理性肝脏退化作为了解肝脏转移生态位的模型，并建议未来研究在退化肝脏中识别的免疫环境是否可以被更广泛地用于治疗转移。在啮齿类动物中，我们确定了正常肝脏中的一个生理过程，该过程创造了转移前的生态位。这种生理机制是由断奶引起的肝脏退化，特征是肝细胞死亡、免疫内流和细胞外基质重塑。在这里，使用断奶诱导的肝脏退化作为生理调节的促进转移的生态位的模型，我们研究了肝脏退化如何支持乳腺癌转移。门静脉注射D2OR(低转移)或D2A1(高转移)小鼠乳腺癌细胞，在BALB/c免疫活性宿主体内诱导肝转移。肿瘤发病率和多样性在退化宿主中增加，但没有证据表明有增殖优势。与未分娩组相比，消退组的D2OR肿瘤细胞外渗、种植和早期存活期并未增加。相反，肿瘤细胞注射后14天观察到退缩转移优势。这种转移优势与诱导退化宿主肝脏的免疫耐受，依赖于生殖状态的肿瘤内免疫成分，以及依赖CD8抑制未分娩宿主的转移有关。我们的发现表明，正常的产后肝脏处于免疫抑制状态，这可以为循环中的乳腺癌细胞提供促进转移的优势。可能与女性相关，因为产后诊断乳腺癌是肝转移的独立预测因子。
Cancer becomes lethal when it metastasizes to secondary sites, and for breast cancer metastasis to the liver is a serious clinical problem. Liver metastasis is promoted, in part, by changes to the liver environment, resulting in the formation of a metastatic niche that supports circulating tumor cells. Understanding how the liver niche support breast cancer cells may lead to development of treatments for patients with metastatic breast cancer. Here, we report that the developmentally regulated process of weaning-induced liver involution increases liver metastasis in cancer cells with otherwise low metastatic potential. Increased metastasis associates with unique immunological properties in the involuting liver, including reduced ability to activate T cells required for tumor cell clearance. These data establish physiologic liver involution as a model to understand the liver metastatic niche and suggest future research into whether the immune milieu identified in the involuting liver could be targeted to treat metastases more generally. In rodents, we identified a physiologic process within the normal liver that creates a pre-metastatic niche. This physiology is weaning-induced liver involution, characterized by hepatocyte cell death, immune influx, and extracellular matrix remodeling. Here, using weaning-induced liver involution as a model of a physiologically regulated pro-metastatic niche, we investigate how liver involution supports breast cancer metastasis. Liver metastases were induced in BALB/c immune competent hosts by portal vein injection of D2OR (low metastatic) or D2A1 (high metastatic) mouse mammary tumor cells. Tumor incidence and multiplicity increased in involution hosts with no evidence of a proliferation advantage. D2OR tumor cell extravasation, seeding, and early survival were not enhanced in the involuting group compared to the nulliparous group. Rather, the involution metastatic advantage was observed at 14 days post tumor cell injection. This metastatic advantage associated with induction of immune tolerance in the involution host liver, reproductive state dependent intra-tumoral immune composition, and CD8-dependent suppression of metastases in nulliparous hosts. Our findings suggest that the normal postpartum liver is in an immune suppressed state, which can provide a pro-metastatic advantage to circulating breast cancer cells. Potential relevance to women is suggested as a postpartum diagnosis of breast cancer is an independent predictor of liver metastasis.
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影响因子：
5.2
作者：
Gordon-Weeks A;Yuzhalin AE
通讯作者：
Yuzhalin AE
DOI：
10.1016/j.jamcollsurg.2008.12.001
发表时间：
2009-03
影响因子：
5.2
作者：
Gnerlich, Jennifer L.;Deshpande, Anjali D.;Jeffe, Donna B.;Sweet, Allison;White, Nick;Margenthaler, Julie A.
通讯作者：
Margenthaler, Julie A.
影响因子：
21.3
作者：
Costa-Silva B;Aiello NM;Ocean AJ;Singh S;Zhang H;Thakur BK;Becker A;Hoshino A;Mark MT;Molina H;Xiang J;Zhang T;Theilen TM;García-Santos G;Williams C;Ararso Y;Huang Y;Rodrigues G;Shen TL;Labori KJ;Lothe IM;Kure EH;Hernandez J;Doussot A;Ebbesen SH;Grandgenett PM;Hollingsworth MA;Jain M;Mallya K;Batra SK;Jarnagin WR;Schwartz RE;Matei I;Peinado H;Stanger BZ;Bromberg J;Lyden D
通讯作者：
Lyden D
影响因子：
3.8
作者：
Callihan, Eryn B.;Gao, Dexiang;Jindal, Sonali;Lyons, Traci R.;Manthey, Elizabeth;Edgerton, Susan;Urquhart, Alexander;Schedin, Pepper;Borges, Virginia F.
通讯作者：
Borges, Virginia F.
影响因子：
7.3
作者：
Cummings, Margaret C.;Simpson, Peter T.;Reid, Lynne E.;Jayanthan, Janani;Skerman, Joanna;Song, Sarah;Reed, Amy E. McCart;Kutasovic, Jamie R.;Morey, Adrienne L.;Marquart, Louise;O'Rourke, Peter;Lakhani, Sunil R.
通讯作者：
Lakhani, Sunil R.